Loss of p53-mediated apoptosis contributes to tumorigenesis and chemoresistance. We have used subtractive hybridization screening to isolate genes up-regulated early in the apoptotic process, following treatment of chemosensitive cells with adriamycin, using matched chemoresistant cells as a control. We isolate a novel gene, named KILLER/DR5, that is up-regulated in chemosensitive cells following exposure to adriamycin, etoposide or ionizing radiation. KILLER/DR5 is a member of the TNF cell death receptor family that activate the caspase cascade through interaction with cytoplasmic adaptors. KILLER/DR5 appears to be regulated by p53 and is an extremely potent suppressor of cancer cell growth through apoptosis induction. We propose to investigate the regulation of KILLER/DR5 gene expression, following DNA damaging radiation. We will investigate the structural requirements within KILLER/DR5, as well as it signaling mechanism for apoptosis. Our studies should lead to important knowledge about the mechanism of radiation induced apoptosis and further efforts directed at rational drug development for cancer.